Orodispersible tablets

ABSTRACT

This invention relates to a an orally disintegrating tablet obtainable by direct compression of a dry powdered mixture, said mixture comprising up to 15% by weight of calcium silicate, at least 50% of a diluent, a disintegrant agent and an active ingredient. It also relates to a process for preparing the tablets by homogeneous blending the specific excipients in powder form and subsequent direct compression of the mixture. Said tablets disintegrate quickly in the cavity of the mouth, in particular in less than 15 seconds.

FIELD OF THE INVENTION

The present invention relates to solid pharmaceutical formulations, inparticular it relates to a tablet for oral administration whichdisintegrates rapidly by the action of saliva in the oral cavity, havingalso good palatability, friability, mechanical strength properties andemploying a conventional manufacturing method to obtain them.

BACKGROUND OF THE INVENTION

The development of solid formulations that disintegrate quickly in themouth without requiring water are very interesting due to the advantagesthat these pharmaceutical formulations provide for patients who havedifficulty in swallowing, such as old people, infants, patients withmental problems and non-cooperative patients, as well as the populationin general; since it makes it possible for the drug to be administeredwithout the need for water. Moreover, since the formulationdisintegrates inside the mouth, the drug may be absorbed in the oral,pharyngeal and gastrointestinal regions. The pre-gastric drug absorptionavoids hepatic first-pass metabolism.

In the European Pharmacopoeia (Ph.Eur.) 5th edition, Supplement 5.2,published in June 2004, orodispersible tablets are defined as non-coatedtablets for placing in the mouth which disintegrate quickly before theyare swallowed. It also establishes 3 minutes as the time under whichthey must disintegrate in the disintegration test for tablets andcapsules, according to the Ph. Eur. 2.9.1. method.

Several technologies are available to produce commercial oralfast-dissolving systems. The technologies are usually grouped accordingto the method employed in the preparation: freeze drying (Zydis®,Quicksolv® and Lyoc®), molding (FlashDose®) and compaction technologies.

Freeze drying (lyophilization) is a process in which a solvent isremoved from a drug solution or a drug suspension containingstructure-forming excipients. The tablets are characterized by a highlyporous network; they quickly absorb water and dissolve, releasing theincorporated drug. The freeze drying process occurs at a lowtemperature, which eliminates the adverse thermal reactions that mayaffect drug stability. However, the freeze-drying process is veryexpensive and problematic when scaling up. In addition, the resultingdosage form is characterised by high friability, low stability at hightemperatures and humidity levels, and by showing poor mechanicalproperties. Moreover, sometimes, special packaging is required.

The molding technology can be based in two different processes: thesolvent method and the heat method. The solvent molding process involvespreparation of a drug solution or suspension that contains a drug andthe excipients and evaporating the solvent at ambient pressure anddrying. In the heat molding method, the tablets are formed using a candyfloss or shearform matrix, which is composed of saccharides orpolysaccarides processed into amorphous floss by the simultaneous actionof flash melting and centrifugal forces. The molding technology allowspreparing high drug dose tablets and the resulting tablets present arapid dissolution. However, because of their low mechanical strength,molded tablets are subject to erosion and breakage during the handlingand opening of the blister pockets. Moreover, taste masking is anadditional requirement with this technology.

The conventional process used to prepare fast-dissolving tablets hassome advantages, such as being a well established technology, having lowmanufacturing cost and allowing easy technology transfer (e.g. easy totransfer to different producers). Many strategies for developing tabletswith high porosity and suitable mechanical strength have been attempted,including: granulation (wet granulation, dry granulation and moldgranulation) followed by compression; and direct compression.

In the granulation process, fast dissolving tablets are prepared bymixing the granules with a superdisintegrant and other appropriateexcipients and compacting to obtain tablets capable of quicklydisintegrating in the mouth with a limited amount of saliva. Formulationbased on this technology is FlashTab® to Prographarm which is describedin European patent EP 0 548 356.

On a related matter, EP1681048 describes an orally disintegrating tabletof olanzapine prepared with granulation as intermediate step andsubsequent compression of the granules. A similar method is alsodisclosed in DE102005009241 and IP. Com. Journal, 2006, but theyincorporate other active ingredients. EP1488811 refers to orallydisintegrating tablets of pravastatin which are obtained by compressionmoulding of prepared granules. EP1674083 discloses fast disintegratingtablets prepared by first granulating a dispersion containing theingredients in a spray-drying device, mixing the obtained granules withthe active ingredient and magnesium stearate and finally, subjecting themixture to a tabletting process.

Although tablets obtained through the granulation methodologydemonstrate rapid dissolution, its rate is correlated to the hardness ofthe tablet and can be slower than freeze-dried tablets. Moreover,possible problems can be related to drug stability after granulation.

Direct compression represents the simplest and most cost-effectivetablet-manufacturing technique from a technological point of view.Fast-dissolving tablets can be prepared by using suitable excipientswith improved properties. Two known formulations based on thistechnology are Ziplets® to Eurand which are described in internationalpatent application WO 99/44580 and DuraSolv® by Cima described in U.S.Pat. No. 6,024,981. Direct compression based technologies uses suitableexcipients with improved properties, most notably superdisintegrantswhich accelerate the rate of disintegration and hence dissolution. Watersoluble excipients and, sometimes, effervescent agents assist in thedisintegration process. Addition of insoluble compounds which increasethe efficiency of the superdisintegrant: the disintegration timedecreases as the amount of hydrophilic insoluble compound increases.

Ziplets® technology is used to obtain taste masking and fast release ofwater-soluble or water insoluble drugs from microcapsules and granules.The resulting fast-dissolving tablets are obtained by direct compressionof mixtures that contain at least one inorganic excipient that isinsoluble in water, for example, calcium phosphate, one or moredisintegrants, for example, crospovidone and optionally, water solubleexcipients. However, the resulting compositions contain a highpercentage of insoluble excipients which leave a high amount of residuein the mouth and jeopardise their palatability.

The DuraSolv® technology is designed to provide stronger tablets withoutpackaging precautions. This technology is based on employment ofconventional non-direct compression fillers (such as dextrose, mannitol,sorbitol, lactose and sucrose) in the form of fine particles thatquickly dissolve without producing a gritty or sandy sensation in themouth.

However, all the above processes for obtaining orodispersible tabletsinvolve, to a greater or lesser extent, the following disadvantages:

-   -   A high content of insoluble excipients or microencapsulated        active ingredients that give the formula a gritty feel after        they have been disintegrated in the oral cavity and,        consequently, problems with palatability.    -   Excessively long disintegration times in comparison with oral        lyophilisates or wafers, which, in general, dissolve in less        than 10 seconds.    -   Insufficient mechanical resistance to resist conventional        packaging and transport operations.

American patent U.S. Pat. No. 6,610,266 describes the preparation ofcalcium metasilicates with low aspect ratio, and its use to preparefast-disintegrating tablets by direct compression. However, largeamounts of this excipient, about 40% by weight, are required forpreparing the tablets, thus negatively affecting the size as well as thepalatability of the tablet.

International application WO03/030868 also discloses the use of calciumsilicate to prepare flashmelt oral dosage formulations. In this case, inaddition to use even higher proportions of said excipient, themanufacturing process is more complex since it comprises a previousgranulation of the ingredients.

Therefore, it is an object of this invention to provide orodispersibletablets which can be dissolved quickly in the oral cavity, whichpresents good palatability properties and that can be obtained byconventional processes, such as direct compression.

BRIEF SUMMARY OF THE INVENTION

The authors of the present invention have surprisingly found that aformulation based on a dry powdered mixture comprising up to 15% byweight, at least 50% by weight of a diluent and a disintegrant, allowspreparing orodispersible tablets by direct compression, withdisintegration times very similar to those obtained using more complextechniques. In fact, the orodispersible tablets can be disintegrated inthe mouth cavity in less than 15 seconds, having also a high mechanicalresistance, a low friability and higroscopicity, which involve importantadvantages with respect to other technologies which require preparingtablets with low resistance and high porosity in order to get shortdisintegration times.

Direct compression provides important advantages over other complextechniques since the active ingredient is not subjected to humidityconditions (water or other solvents) or to high temperatures, conditionswhich are known to diminish the stability of the oral formulation. Inaddition, due to its simplicity, it only requires simple machineryleading to a reduction in economic and energetic manufacturing costs.

Unlike other typical formulations used in direct compression, which arenot only rather expensive but also very coarse and granular in natureresulting in a coarse dispersion in the mouth, the formulation used inthe invention to prepare the orodispersable tablets provides an improvedpalatability. This technical feature is mainly derived from theincorporation of calcium silicate as excipient which avoids theremaining excipients to agglutinate forming agglomerates which renderdifficult the dispersion of the tablet in the mouth leading to anunpleasant taste and therefore to a diminished patient compliance.

Furthermore, one of the main advantages conferred by this formulation isthe possibility of providing tablets with a thickness less than 30% ofits major diameter, thus favouring the disintegration in the mouth andalso improving the palatability. These features make even easier theadministration of active ingredients to patients who have difficulty inswallowing. In addition, since the amount of calcium silicate is verylow, it is also possible to elaborate tablets with a high content ofactive ingredient, without affecting the final size of the tablet.

Therefore, in a first aspect, the present invention relates to an orallydisintegrating tablet obtainable by direct compression of a dry powderedmixture, said mixture comprising:

-   -   up to 15% by weight of calcium silicate;    -   at least 50% by weight of a diluent,    -   at least a disintegrant; and    -   at least an active ingredient.

Moreover, the inventors have found that by incorporating an effervescentcomponent in the formulation, an even higher improvement in thepalatability of the tablets is achieved. Consequently, the formulationof the invention can further comprise an effervescent component.

A second aspect of the present invention relates to a process for thepreparation of a tablet as defined above, which comprises:

-   -   a) mixing the dry powdered ingredients in the required amount,        and    -   b) applying direct compression to the mixture obtained in step        a).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to an orally disintegrating tabletobtainable by direct compression of a dry powdered mixture, said mixturecomprising up to 15% by weight of calcium silicate, at least 50% byweight of a diluent, at least a disintegrant, and at least an activeingredient. This solid formulation rapidly disintegrates in the mouth ofa patient, also providing a positive organoleptic sensation sincenon-water soluble components are considerably minimized.

The orodispersible tablet is advantageously used in cases whereadministration without water is necessary, cases of administration topatients who have difficulty in swallowing tablets, or cases ofadministration to the elderly or to children where there is a fear ofblocking the throat if it is unusual tablet form. The orodispersibletablets can be safely administered orally to humans.

Calcium Silicate

In the context of the present invention, by the term “calcium silicate”it is understood a material, natural or synthetic, of formula CaSiO₃characterized by having a ratio of moles of calcium to moles of silicon,of about 1.0. In a particular embodiment, the calcium silicate used inthe present invention is a naturally-occurring mineral, also known aswollastonite, having a CaO/SiO₂ molar ratio ranging from about 0.8 to1.3. There exist different crystalline types of wollastonite mineralsuch as, type 1A (wollastonite), 2M (parawollastonite) and 7M(pseudowollastonite), being type 1A the most prevalent naturally form.These naturally-occurring calcium silicates have a crystalline form andhigh aspect ratios (above 3:1 and even above 20:1), that providerigidity and strength.

Particularly preferred is the use of calcium silicate in crystallineform, more preferably ortho-, meta- and alpha-triclinic forms of calciumsilicate. Examples of crystalline alpha triclinic calcium silicate arethose commercially available from Aldrich Chemical, which meets thefollowing specifications: 1.3 m²/g surface area, 0.63 g/cc bulk density,2.90 g/cc true density and <1% w/w volatiles, and those from J.M. HuberInc., Tomita Pharmaceutical Co., and Aldrich Chemical which meets thefollowing specifications: 1.0 to 15 m²/g surface area, 0.50 to 0.63 g/ccbulk density, 2.40 to 2.90 g/cc true density and <1% w/w volatiles.Examples of ortho- and meta-calcium silicate forms are available fromAlfa-Aesar and cover the following range of specifications for calciumsilicate: 0.98 to 2.5 m²/g surface area, 0.49 to 0.90 g/cc bulk density,2.90 to 3.30 g/cc true density and <1% w/w volatiles.

In another preferred embodiment, the calcium silicate used in theformulation is amorphous and it is generally produced synthetically. Thesilica source can be selected from naturally occurring pure forms ofcrystalline silicon dioxide or from synthetic amorphous silicon dioxide.The preferred form of silica is amorphous silicon dioxide, such asprecipitated silica, silica gel, fumed silica or colloidal silica. Thecalcium source may be selected from the group including, silicates,oxides, carbonates, sulfates, hydroxides and salts or mixtures thereof.

Examples of amorphous calcium silicate are those commercially availablefrom Celite Corp (micro-cel C) and J.M. Huber (Hubersorb 250NF andHubersorb 600NF), which covers the following specifications: 190 to 210m²/g surface area, 0.07 to 0.13 g/cc bulk density, 1.70 to 2.5 g/cc truedensity and 1% to 14% w/w volatiles.

In addition to the naturally-occurring or synthetic calcium silicatesdiscussed above, it is also possible to use in the formulation syntheticcalcium metasilicates as those disclosed in U.S. Pat. No. 6,610,266.Said calcium metasilicates are characterized by having a low aspectratio and forming structured aggregates of uniform particles yieldinghigh water absorption characteristics. Specifically, this low aspectratio (average major axial diameter/average minor axial diameter) of thecalcium metasilicate is between about 1:1 to about 2.5:1, preferablyfrom about 1:1 to about 1.5:1, and an water absorption of from about 20ml/100 g to about 220 ml/100 g, preferably from about 20 ml/100 g toabout 100 ml/100 g. The major axis is perpendicular, although notnecessarily coplanar, with the minor axis. The calcium metasilicate canbe dehydrated (or “calcined”).

In the context of the present invention, the term calcium silicate alsoincludes mixtures of the different grades of the calcium silicatesmentioned above.

Diluent

The formulation according to the present invention also comprises atleast 50% by weight of a diluent. Examples of diluents which can be usedin the invention include, without limitation, saccharides such asmonosaccharides, oligosaccharides or polysaccharides, and/or theiroxidised and/or reduced forms; ribose, lactose in its various forms,anhydrous, monohydrate, agglomerated forms or atomised forms; sugaralcohols such as mannitol, maltol, sorbitol, maltitol, xylitol, isomaltand erythritol, cellulose powder, microcrystalline cellulose, silifiedmicrocrystalline cellulose or derivatives of cellulose modifiedchemically, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose; isomalt, starch, sucrose, pharmaceutically acceptableinorganic compounds such as dibasic calcium phosphate, carbonates ofcalcium or of magnesium, magnesium oxide, sugar alcohols selected frommannitol, sorbitol, maltitol, maltol, isomalt, xylitol, erythritol, ormixtures thereof. In a preferred embodiment, the diluent is anoligosacharide or a sugar alcohol of medium or low solubility selectedfrom maltol, and mannitol and mixtures thereof. More preferably, thediluent is selected from lactose, lactose monohydrate and mannitol.

Disintegrant

By the term “disintegrant” it is understood a compound which facilitatesthe break-up of a tablet when it is placed in aqueous environment.Disintegrants once in contact with water, swell, hydrate, change involume or form to produce a disruptive force that opposes the efficiencyof the binder/s causing the compressed table to break apart. They belongto different morphological classes and posses different functionalityproperties. Suitable for use in the formulation of the invention includenatural starches, such as maize starch and potato starch; directlycompressible starches such as starch 1500; modified or pregelatinizedstarches such as carboxymethylstarches and sodium starch glycolate;natural or chemically-modified cellulose, especially crosslinked sodiumcarboxymethyl cellulose (croscarmellose sodium) or low substitutedhydroxypropyl cellulose; microcrystalline cellulose; gum, especiallyagar gum, and guar gum; alginic acid or salts thereof; acetates andcitrates; sugars (especially lactose, mannitol and sorbitol); aluminumoxide; synthetic polymers such as cross-linked polyvinylpyrrolidones,specially crospovidone.

In a preferred embodiment of the invention, the disintegrant agent iscrospovidone and croscarmellose sodium.

Active Ingredient

The active ingredient can include pharmaceutical ingredients, vitamins,minerals and dietary supplements. In a particular embodiment, the activeingredient is a pharmaceutical ingredient. Pharmaceutical ingredientsthat may be used include, but are not limited to, gastrointestinalfunction conditioning agents, anti-inflammatory agents, analgesics,agents for erectile dysfunction therapy, anti-depressants, sedatives,hypnotics, neuroleptics, anti-migraines, antihistaminic agents, forexample loratadine, desloratadine, pseudoephedrine, cetirizine andmixture thereof, anti-bacterial agents, antiviral agents, cardiovascularagents, diuretics, anti-hypertensive agents anti-hypolipidemic agents,anti-ulcer agents, antiemetics, anti-asthmatic agents, anti-depressants,anti-thrombotic agents, chemotherapeutic agents, hormones,anti-helmintic agents, anti-diabetic agents, corticosteroids, peptides,proteins, recombinant drugs and mixtures thereof.

In a preferred embodiment, the pharmaceutical ingredient is selectedfrom the group consisting of loratadine, desloratadine, aripiprazole,olanzapine, risperidone, ondansetron, zolmitriptan, rizatriptan,frovatriptan, eletriptan, almotriptan and salts thereof.

In another particular embodiment of the invention, the active ingredientis selected from a vitamin, a mineral, a dietary supplement and mixturesthereof.

As used in this disclosure, the term “vitamin” refers to trace organicsubstances that are required in the diet. Examples of vitamins include,without limitation, thiamine, riboflavin, nicotinic acid, pantothenicacid, pyridoxine, biotin, folic acid, vitamin B₁₂, lipoic acid, ascorbicacid, vitamin A, vitamin D, vitamin E and vitamin K. The term vitaminalso includes choline, carnitine, and alpha, beta and gamma carotenes.

The term “mineral” refers to inorganic substances, metals, and the likerequired in the human diet. Examples of minerals include, withoutlimitation, calcium, iron, zinc, selenium, copper, iodine, magnesium,phosphorous, chromium and the like, and mixtures thereof.

The term “dietary supplement” as used herein means a substance which hasan appreciable nutritional effect when administered in small amounts.Dietary supplements include, without limitation, ingredients such aspollen, bran, wheat germ, kelp, cod liver oil, ginseng, fish oils, aminoacids, proteins and mixtures thereof. As will be appreciate, dietarysupplements may incorporate vitamins and minerals.

In general, the amount of active ingredient incorporated in theformulation may be selected according to known principles of pharmacy.An effective amount of pharmaceutical ingredient is specificallycontemplated. By the term “effective amount” it is understood that theamount or quantity of a drug or pharmaceutically active substance whichis sufficient to elicit the required therapeutic response. As used withreference to a vitamin or mineral, the term “effective amount” means anamount at least about 10% of the recommended daily dose.

The amount of the active ingredient used can vary greatly. Those ofordinary skill in the art will appreciate that the physicalcharacteristics of the active ingredient, the size of the tablet and therequirements of other ingredients will directly influence its limitingcontent in the formulation. However, generally, the active ingredientdoes not exceed 30% by weight, preferably from 1 to about 20% by weight,most preferably from 1 to about 15% by weight based on the total weightof the formulation. In addition, the authors of the present inventionhave found that by incorporating an effervescent component in theformulation of the invention an improvement of the palatability of thetablets is obtained, thus providing a pleasant organoleptic sensation.Therefore, the formulation of the present invention can further comprisean effervescent component. Suitable effervescent components that can beused in the formulation of the invention are a mixture comprising a CO₂donor and an organic acid. Typical CO₂ donors include carbonates andbicarbonates such as sodium bicarbonate, potassium bicarbonate, sodiumcarbonate and potassium carbonate. Examples of organic acids include,without limitation, citric, malic, tartaric, adipic and fumaric acid.

The pharmaceutical composition of the present invention can also includeother conventional excipients like surfactants, flavouring agents,lubricants, sweeteners, glidants, antiadherants and mixtures thereof,which affect the elegancy and performancy of the orodispersiblepharmaceutical compositions. The additional excipients used in saidformulation are present in small amounts, e.g. generally less than 10%,preferably 5% of the total mass of the tablet.

The lubricant is used herein as an additional excipient that can affectthe performance of an orodispersible pharmaceutical composition.Suitable examples of lubricants include but are not limited to talc,sodium benzoate, sodium stearyl fumarate (Pruv), calcium stearate,magnesium stearate, zinc stearate, glyceryl behenate, stearic acid andglyceryl monostearate. Preferred lubricant for the composition of thepresent invention is sodium stearyl fumarate or magnesium stearate orcombination thereof. Preferably the lubricant(s) of the presentinvention are used in an amount of about 0.25 to 5% by weight.

Suitable flavouring agents used in the composition of the presentinvention include but are not limited to strawberry, cherry, orange,peppermint, black currant, banana, raspberry, red fruits, wild berriesand caramel flavour. Preferably the flavouring agents of the presentinvention are used in an amount of less than 2% by weight.

The sweetener may be selected from the group especially comprisingaspartame, potassium acesulfame, sodium saccharinate, neohesperidinedihydrochalcone, sucralose, sucrose, fructose, monoammoniumglycyrrhizinate, and mixtures thereof. Preferably the sweetener of thepresent invention is used in an amount of about 1 to 2% by weight.

The orally disintegrating tablet of the invention can be rapidlydisintegrated in the mouth, having also a high mechanical resistance andlow friability. The term friability refers to an index which provides ameasure of the ability of a tablet to withstand both shock and abrasionwithout crumbling the handling of manufacturing, packaging, shipping andconsumer use. The orodispersible tablet of the present inventionpresents a friability no greater than 1%, preferably no greater than0.8%.

The formulation used in the invention allows preparing orodispersibletablets with a very low thickness, thus increasing the tablet surfaceand consequently the speed of disintegration. In a particular embodimentof the invention, the orodispersible tablet has a thickness less than30% of its major diameter. This small thickness facilitates thedisintegration of the tablet as well as its palatability. Thus, in aparticular embodiment, the orodispersible tablet of the inventiondisintegrates in less than 20 seconds, more preferably in less than 15seconds, even more preferably in less than 10 seconds.

The orally disintegrating tablet of the present invention is prepared bydirect compression of a dry powdered mixture. The term “directcompression” is used in the context of the invention to define a processby which tablets are compressed directly from powder blends of theactive ingredient and the excipients (including diluents, fillers,disintegrants and lubricants), which flow uniformly into a die cavityand form a firm compact. No pretreatment of the powder blend by wet ordry granulation procedures is applied. When potent drugs areincorporated in the formulation, these can be sprayed out of solutiononto one of the excipients.

By the term “dry powdered mixture” it is understood a mixture ofingredients in powder form, wherein said ingredients have beenpreviously and independently passed through a sieve with mesh size lowerthan 650 μm, that guarantees a mean particle size lower than that size,without having been subjected to any granulation process, dissolution ordispersion in a liquid medium.

In a particular embodiment, the calcium silicate, the diluent, thedisintegrant agent and the active ingredient are homogeneously mixedtogether in powder form to provide a homogeneous mixture. The mixture isthen subjected to direct compression to provide a solid preparation inthe form of a tablet. For example, the powder mixture is fed to the dieof a tablet press and sufficient pressure is applied to form the solidtablet. Such pressure can vary, and typically ranges about 1.000-20.000N, being particularly Preferable 3.000-15.000 N. Direct compression isthe easiest way of manufacturing tablets and has the great advantage ofhaving a low manufacturing cost. Moreover, it uses conventionalequipment, commonly available excipients and a limited number of processsteps.

The resulting compressed solid preparation possesses a suitable strengthAND hardness and does not disintegrate during distribution and storage.

The following non-limiting examples will further illustrate specificembodiments of the invention. They are, however, not intended to belimiting the scope of the present invention in any way.

EXAMPLES Example 1

Orodispersible tablets were made according to the method defined belowusing the formulation having the ingredients shown in table I:

TABLE I mg % (w/w) 1. Olanzapine 10.00 mg  12.50%  2. Lactosemonohydrate 54.61 mg  68.26%  3. Hydroxypropylcellulose 3.20 mg 4.00%low-substituted 4. Crospovidone 2.40 mg 3.00% 5. Calcium silicate 7.20mg 9.00% 6. Aspartame 1.07 mg 1.33% 7. Banana Flavor 0.16 mg 0.20% 8.Orange Flavor 0.16 mg 0.20% 9. Colloidal anhydrous silica 0.40 mg 0.50%10. Magnesium stearate 0.80 mg 1.00% Total   80 mg  100%

Manufacturing Method

The orodispersible tablet was obtained according to the followingprocedure:

-   -   a) the components of the formulation were weighted;    -   b) components 4 and 5 were sieved through a screen with a mesh        size of 0.5-0.6 mm;    -   c) the materials of stage “b” were mixed in a suitable container        until a homogeneous mixture was obtained;    -   d) components 1, 2, 3, 6, 7, 8 and 9 were sieved through a        screen with a mesh size of 0.5-0.6 mm;    -   e) the materials of stage “d” were mixed with the blend obtained        in stage “c” in a suitable container until a homogeneous mixture        was obtained;    -   f) the component 10 was sieved through a screen with a mesh size        of 0.3-0.4 mm, it was incorporated into the homogeneous mixture        obtained in section “e”, and the whole was mixed in a suitable        container for approximately 5 minutes    -   g) the mixture powder obtained in stage “f” was compressed in a        tabletting machine equipped with suitable punches.

Disintegration time 10 sec. Weight 80 mg Resistance to crushing 33 NFriability <0.1% Thickness 1.77 mm

Disintegration Time

The disintegration time has been measured according to the followingprocedure.

A filter paper was placed on the bottom of Petri dish and then purifiedwater was poured to achieve a homogeneous humectation. The tabletprepared as defined above was placed on the humectated paper and thecomplete disintegrating time of the tablet was measured. The test wasdone six times and the results were averaged.

Tablet Weight

20 tablets were weighted in an automatic balance and the average masswas calculated.

Resistance to Crushing

The resistance to crushing of 10 tablets is determined according to theequipment and method described in the Ph. Eur. 2.9.8.

Friability

The friability of the tablets is performed according to the equipmentand method described in the Ph. Eur. 2.9.7.

Thickness

The thickness of a tablet is the distance between the middle point ofthe two surfaces of the tablet and it is measured with a micrometer.

Example 2

The tablet was prepared according to the procedure described below usingthe formulation having the ingredients shown in table II:

TABLE II mg % (w/w) 1. Olanzapine 10.00 mg  13.33%  2. Lactosemonohydrate 40.98 mg  54.63%  3. Hydroxypropylcellulose 3.00 mg 4.00%low-substituted 4. Crospovidone 3.00 mg 4.00% 5. Calcium silicate 9.00mg 12.00%  6. Aspartame 1.00 mg 1.33% 7. Calcium carbonate 3.00 mg 4.00%8. Tartaric acid 3.75 mg 5.00% 9. Banana Flavor 0.15 mg 0.20% 10.Colloidal anhydrous silica 0.38 mg 0.50% 11. Magnesium stearate 0.75 mg1.00% Total   75 mg  100%

Manufacturing Method

The orodispersible table was obtained according to the followingprocedure:

-   -   a) components of the formulation were weighted;    -   b) components 4 and 5 were sieved through a screen with a mesh        size of 0.5-0.6 mm;    -   c) the materials of stage “b” were mixed in a suitable container        until a homogeneous mixture has been obtained;    -   d) components 1, 2, 3, 6, 7, 8, 9 and 10 were sieved through a        screen with a mesh size of 0.5-0.6 mm;    -   e) the materials of stage “d” were mixed with the blend obtained        in stage “c” in a suitable container until a homogeneous mixture        was obtained;    -   f) the component 11 was sieved through a screen with a mesh size        of 0.3-0.4 mm, it was incorporated into the homogeneous mixture        obtained in section “e”, and the whole was mixed in a suitable        container for approximately 5 minutes;    -   g) the mixture powder obtained in stage “f” was compressed in a        tabletting machine equipped with suitable punches.

Disintegration time 11 sec. Weight 75 mg Resistance to crushing 36 NFriability 0.17% Thickness 1.65 mm

Example 3

The tablet was prepared according to the procedure described below usingthe formulation having the ingredients shown in table III:

TABLE III PR-42 mg % (w/w) 1. Zolmitriptan 2.5 2.77 2. Mannitol granular73.45 81.61 3. Crospovidone 4.5 5 4. Calcium silicate 6.3 7 5. Aspartame0.9 1 6. Orange Flavour 0.9 1 7. Strawberry Flavour 0.1 0.11 8.Magnesium Stearate 1.35 1.5 Total 90 100

Manufacturing Method

The orodispersible table was obtained according to the followingprocedure:

-   -   a) the components of the formulation were weighted;    -   b) component 1, enough amount of 2 to achieve a homogeneous        mixture, 3 and 4 were sieved through a screen with a mesh size        of 0.5-0.6 mm;    -   c) the materials of stage “b” were then mixed together in a        suitable container until a homogeneous mixture was obtained;    -   d) the rest of component 2, and components 5, 6, and 7 were        sieved through a screen with a mesh size of 0.5-0.6 mm;    -   e) the materials of stage “d” were mixed together in a suitable        container until a homogeneous mixture was obtained;    -   f) component 8 was sieved through a screen with a mesh size of        0.5-0.6 mm, it was incorporated into the homogeneous mixture        obtained in section “e”, and the whole was mixed in a suitable        container for approximately 2 minutes;    -   g) the mixture powder obtained in stage “f” was compress in a        tabletting machine equipped with suitable punches.

Disintegration time 9 sec. Mean tablet weight 90 mg Tablet crushingstrength 17 N Tablet friability 0.45% Tablet thickness 2.1 mm

Example 4

The tablet was prepared according to the procedure described below usingthe formulation having the ingredients shown in table IV:

TABLE IV mg % (w/w)  1. Ondansetron base 4.00 mg 5.30%  2. Spry driedmannitol 42.38 mg  56.50%   3. Microcrystalline cellulose 11.25 mg 15.00%   4. Sodium croscarmellose 2.25 mg 3.00%  5. Calcium silicate6.75 mg 9.00%  6. Aspartame 1.00 mg 1.30%  7. Calcium carbonate 3.39 mg4.52%  8. Tartaric acid 2.24 mg 2.98%  9. Peppermint flavour 1.00 mg1.30% 10. Magnesium stearate 0.75 mg  1.0% Total   75 mg 100.00% 

Manufacturing Method

The orodispersible table was obtained according to the followingprocedure:

-   -   a) the components of the formulation were weighted;    -   b) components 4 and 5 were sieved through a screen with a mesh        size of 0.5-0.6 mm;    -   c) the materials of stage “b” were mixed in a suitable container        until a homogeneous mixture was obtained;    -   d) components 1, 2, 3, 6, 7, 8, 9 and 10 were sieved through a        screen with a mesh size of 0.5-0.6 mm;    -   e) the materials of stage “d” were mixed with the blend obtained        in stage “c” in a suitable container until a homogeneous mixture        was obtained;    -   f) the component 10 was sieve through a screen with a mesh size        of 0.3-0.4 mm, it was incorporated into the homogeneous mixture        obtained in section “e”, and the whole was mixed in a suitable        container for approximately 5 minutes;    -   g) the mixture powder obtained in stage “f” was compressed in a        tabletting machine equipped with suitable punches.

Disintegration time 9 sec. Weight 75 mg Resistance to crushing 34 NFriability 0.20% Thickness 1.65 mm

Example 5

The tablet was prepared according to the procedure described below usingthe formulation having the ingredients shown in table V:

TABLE V mg % (w/w) 1. Ondansetron base 4.00 mg 10.00%  2. Lactosemonohydrate 27.95 mg  69.88%  3. Hydroxypropylcellulose 1.60 mg 4.00%low-substituted 4. Crospovidone 1.20 mg 3.00% 5. Calcium silicate 3.60mg 9.00% 6. Aspartame 0.53 mg 1.33% 7. Peppermint flavour 0.52 mg 1.30%8. Colloidal anhydrous silica 0.20 mg 0.50% 9. Magnesium stearate 0.40mg 1.00% Total   40 mg  100%

Manufacturing Method

The orodispersible table was obtained according to the followingprocedure:

-   -   a) the components of the formulation were weighted;    -   b) components 4 and 5 were sieved through a screen with a mesh        size of 0.5-0.6 mm;    -   c) the materials of stage “b” were mixed in a suitable container        until a homogeneous mixture was obtained;    -   d) components 1, 2, 3, 6, 7 and 8 were sieved through a screen        with a mesh size of 0.5-0.6 mm;    -   e) the materials of stage “d” were mixed with the blend obtained        in stage “c” in a suitable container until a homogeneous mixture        was obtained;    -   f) the component 9 was sieved through a screen with a mesh size        of 0.3-0.4 mm, it was incorporated into the homogeneous mixture        obtained in section “e”, and the whole was mixed in a suitable        container for approximately 5 minutes;    -   g) the mixture powder obtained in stage “f” was compressed in a        tabletting machine equipped with suitable punches.

Disintegration time 6 sec. Weight 40 mg Resistance to crushing 21 NFriability 0.34% Thickness 1.02 mm

Example 6

The tablet was prepared according to the procedure described below usingthe formulation having the ingredients shown in table VI:

TABLE VI mg % (w/w) 1. Risperidone 2.00 mg 2.50% 2. Lactose monohydrate64.3 mg 80.40%  3. Crospovidone 2.50 mg 3.10% 4. Calcium silicate 7.50mg 9.40% 5. Sodium Cyclamate 2.00 mg 2.50% 6. Cherry Flavor 0.40 mg0.50% 7. Colloidal anhydrous silica 0.40 mg 0.50% 8. Magnesium stearate0.90 mg 1.10% Total   80 mg  100%

Manufacturing Method

-   -   a) the components of the formulation were weighted;    -   b) components 3 and 4 were sieved through a screen with a mesh        size of 0.5-0.6 mm;    -   c) the materials of stage “b” were mixed in a suitable container        until a homogeneous mixture was obtained;    -   d) components 1, 2, 5, 6 and 7 were sieved through a screen with        a mesh size of 0.5-0.6 mm;    -   e) the materials of stage “d” were mixed with the blend obtained        in stage “c” in a suitable container until a homogeneous mixture        was obtained;    -   f) the component 8 was sieved through a screen with a mesh size        of 0.3-0.4 mm, it was incorporated into the homogeneous mixture        obtained in section “e”, and the whole was mixed in a suitable        container for approximately 5 minutes    -   g) the mixture powder obtained in stage “f” was compressed in a        tabletting machine equipped with suitable punches.

Disintegration time 12 sec. Weight 80 mg Resistance to crushing 37 NFriability <0.1% Thickness 1.80 mm

1. An orally disintegrating tablet obtained by direct compression of adry powdered mixture, said mixture comprising: up to 15% by weight ofcalcium silicate; at least 50% by weight of a diluent, wherein saiddiluent is mannitol; at least one disintegrant; and zolmitriptan as anactive ingredient, wherein said orally disintegrating tablet presents afriability no greater than 1% and a disintegration time of less than 20seconds, and wherein the dry powder mixture has not been subjected toany granulation process, dissolution, or dispersion in a liquid medium.2. The tablet according to claim 1, wherein the tablet's thickness isless than 30% of the tablet's major diameter.
 3. (canceled)
 4. Thetablet according to claim 1, wherein the calcium silicate iscrystalline.
 5. The tablet according to claim 1, wherein the calciumsilicate is ortho-, meta- or alpha triclinic-calcium silicate.
 6. Thetablet according to claim 1, wherein said calcium silicate is amorphous.7. (canceled)
 8. (canceled)
 9. The tablet according to claim 1, whereinthe disintegrant is selected from the group consisting of crospovidone,sodium croscarmellose, sodium starch glycolate, low-substitutedhydroxypropyl cellulose and pregelatinized starch.
 10. The tabletaccording to claim 9, wherein the disintegrant is crospovidone or sodiumcroscarmellose.
 11. (canceled)
 12. (canceled)
 13. (canceled)
 14. Thetablet according to claim 1, wherein the powdered mixture furthercomprises an effervescent component.
 15. A process for the preparationof a tablet as defined in claim 1, which comprises: a) mixing the drypowdered ingredients in the required amount, and b) applying directcompression to the mixture obtained in step a), wherein the mixtureobtained in step a) has not been subjected to any granulation process,dissolution, or dispersion in a liquid medium.
 16. The tablet accordingto claim 1, wherein the dry powder comprises from 1 to 20% by weight ofzolmitriptan.
 17. The tablet according to claim 1, wherein said calciumsilicate, mannitol diluent, at least one disintegrant, and zolmitriptanhave been previously and independently passed through a sieve with meshsize lower than 650 μm.
 18. The process of claim 15, wherein saidcalcium silicate, mannitol diluent, at least one disintegrant, andzolmitriptan have been previously and independently passed through asieve with mesh size lower than 650 μm.
 19. The tablet according toclaim 1, wherein the mixture comprises up to 10 weight % of calciumsilicate.